US6413964B1ExpiredUtility
Inhibitors of prenyl-protein transferase
Priority: Jan 12, 2000Filed: Jan 9, 2001Granted: Jul 2, 2002
Est. expiryJan 12, 2020(expired)· nominal 20-yr term from priority
A61P 35/00A61P 9/04C07D 515/08A61P 13/12
71
PatentIndex Score
6
Cited by
26
References
18
Claims
Abstract
The present invention is directed to peptidomimetic macrocyclic compounds of the formula A:wherein W is a heterocycle, V is a heterocycle or aryl moiety and Z1 is a suitably substituted aryl or heterocycle moiety. The instant compounds inhibit prenyl-protein transferase and the prenylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting prenyl-protein transferase and the prenylation of the oncogene protein Ras.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. A compound of the formula A:
wherein:
R 1a , R 1b , R 1c and R 1d are independently selected from:
a) hydrogen,
b) aryl, heterocycle, C 3 -C 10 cycloalkyl, R 10 O—, R 11 S(O) m —, R 10 C(O)NR 10 —, (R 10 ) 2 N—C(O)—, CN, NO 2 , (R 10 ) 2 N—C(NR 10 )—, R 10 C(O)—, R 10 C(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —,
c) unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 2 -C 6 alkenyl or unsubstituted or substituted C 2 -C 6 alkynyl, wherein the substituent on the substituted C 1 -C 6 alkyl, substituted C 2 -C 6 alkenyl or substituted C 2 -C 6 alkynyl is selected from unsubstituted or substituted aryl, heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 10 O—, R 11 S(O) m —, R 10 C(O)NR 10 —, (R 10 ) 2 N—C(O)—, CN, (R 10 ) 2 N—C(NR 10 )—, R 10 C(O)—, R 10 OC(O)—, —N(R 10 ) 2 , and R 11 OC(O)—NR 10 —,
or two R 1a s, two R 1b s or two R 1c s, on the same carbon atom may be combined to form —(CH 2 ) t —;
R 2a , R 2b , R 3a and R 3b are independently selected from H; unsubstituted or substituted C 1-8 alkyl, unsubstituted or substituted C 2-8 alkenyl, unsubstituted or substituted C 2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle,
wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C 1-4 alkyl,
b) (CH 2 ) p OR 6 ,
c) (CH 2 ) p NR 6 R 7 ,
d) halogen,
e) CN,
2) C 3-6 cycloalkyl,
3) OR 6 ,
4) SR 4 , S(O)R 4 , SO 2 R 4 ,
5) —NR 6 R 7
11) —SO 2 —NR 6 R 7
15) N 3 , or
16) F; or
R 2a and R 3a are attached to the same carbon atom and are combined to form —(CH 2 ) u — wherein one of the carbon atoms is optionally replaced by a moiety selected from O, S(O) m , —NC(O)—, and —N(COR 10 )—; and
R 2a and R 3a are optionally attached to the same carbon atom;
R 4 is selected from C 1-4 alkyl, C 3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
a) C 1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
f) —SO 2 R 11 ,
g) N(R 10 ) 2 , or
h) C 1-4 perfluoroalkyl;
R 5 , R 6 and R 7 are independently selected from:
1) hydrogen,
2) R 10 C(O)—, or R 10 OC(O)—, and
3) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more substituents selected from:
a) R 10 O—,
b) aryl or heterocycle,
c) halogen,
d) R 10 C(O)NR 10 —,
f) —SO 2 R 11
g) N(R 10 ) 2 ,
h) C 3-6 cycloalkyl,
i) C 1 -C 6 perfluoroalkyl,
j) (R 10 ) 2 N—C(NR 10 )—,
k) R 10 OC(O)—,
l) R 11 OC(O)NR 10 —,
m) CN, and
n) NO 2 ; or
R 6 and R 7 may be joined in a ring; and independently,
R 5 and R 7 may be joined in a ring;
R 8 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 perfluoroalkyl, F, Cl, Br, R 12 O—, R 11 S(O) m —, R 10 C(O)NR 10 —, (R 10 ) 2 NC(O)—, R 10 2 N—C(NR 10 )—, CN, NO 2 , R 10 C(O)—, R 10 OC(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —, and
c) C 1 -C 6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 perfluoroalkyl, F, Cl, Br, R 10 O—, R 11 S(O) m —, R 10 C(O)NH—, (R 10 ) 2 NC(O)—, R 10 2 N—C(NR 10 )—, CN, R 10 C(O)—, R 10 OC(O)—, —N(R 10 ) 2 , or R 10 OC(O)NH—;
R 9 is selected from:
a) hydrogen,
b) C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O—, R 11 S(O) m —, R 10 C(O)NR 10 —, (R 10 ) 2 NC(O)—, R 10 2 N—C(NR 10 )—, CN, NO 2 , R 10 C(O)—, R 10 OC(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —, and
c) C 1 -C 6 alkyl unsubstituted or substituted by C 1 -C 6 perfluoroalkyl, F, Cl, Br, R 10 O—, R 11 S(O) m —, R 10 C(O)NR 10 —, (R 10 ) 2 NC(O)—, R 10 2 N—C(NR 10 )—, CN, R 10 C(O)—, R 10 C(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —;
R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl, unsubstituted or substituted aryl and unsubstituted or substituted heterocycle;
R 11 is independently selected from C 1 -C 6 alkyl unsubstituted or substituted aryl and unsubstituted or substituted heterocycle;
R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 3 perfluoroalkyl, unsubstituted or substituted benzyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, and C 1 -C 6 alkyl substituted with unsubstituted or substituted aryl or unsubstituted or substituted heterocycle;
A 1 is selected from a bond, —C(O)—, —C(O)NR 10 —, —NR 10 C(O)—, O, —N(R 10 )—, —S(O) 2 N(R 10 )—, —N(R 10 )S(O) 2 —, and S(O) m ;
A 2 is selected from a bond, —C(O)—, —C(O)NR 10 —, —NR 10 C(O)—, O, —N(R 10 )—, —S(O) 2 N(R 10 )—, —N(R 10 )S(O) 2 —, NR 10 C(O)NR 10 —, S(O) m and —C(R 1 c) 2 —;
G 1 , G 2 and G 3 are independently selected from H 2 and O;
W is heterocycle;
V is selected from:
a) heterocycle, and
b) aryl;
X is selected from: abond, —C(O)—, —C(O)NR 10 —, —NR 10 C(O)—, —NR 10 C(O)—O—, —O— C(O)NR 10 —, —NR 10 C(O)NR 10 —, O, —N(R 10 )—, —S(O) 2 N(R 10 )—, —N(R 10 )S(O) 2 — and S(O) m ;
X 1 is selected from: a bond, —C(O)—, —NR 10 C(O)—, —N(R 10 )S(O) 2 — and S(O) 2 ;
Y is selected from a bond, —C(═O)—, —C(O)NR 10 —, —C(O)O—, or —S(═O) m ;
Z 1 is selected from unsubstituted or substituted aryl and unsubstituted or substituted heterocycle, wherein the substituted aryl or substituted heterocycle is substituted with one or more of:
1) C 1-8 alkyl, C 2-8 alkenyl or C 2-8 alkynyl, unsubstituted or substituted with:
a) C 1-4 alkoxy,
b) NR 6 R 7 ,
c) C 3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
f) —S(O) m R 4 ,
g) —C(O)NR 6 R 7 , or
h) C 1-4 perfluoroalkyl;
2) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle,
3) halogen,
4) OR 6 ,
5) NR 6 R 7 ,
6) CN,
7) NO 2 ,
8) CF 3 ;
9) —S(O) m R 4 ,
10) —OS(O) 2 R 4 ,
11) —C(O)NR 6 R 7 ,
12) —C(O)OR 6 , or
13) C 3 -C 6 cycloalkyl;
Z 2 is selected from a bond, unsubstituted or substituted aryl and unsubstituted or substituted heterocycle, wherein the substituted aryl or substituted heterocycle is substituted with one or more of:
1) C 1-8 alkyl, C 2-8 alkenyl or C 2-8 alkynyl, unsubstituted or substituted with:
a) C 1-4 alkoxy,
b) NR 6 R 7 ,
c) C 3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
f) —S(O) m R 4 ,
g) —C(O)NR 6 R 7 , or
h) C 1-4 perfluoroalkyl;
2) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle,
3) halogen,
4) OR 6 ,
5) NR 6 R 7 ,
6) CN,
7) NO 2 ,
8) CF 3 ,
9) —S(O) m R 4 ,
10) —OS(O) 2 R 4 ,
11) —C(O)NR 6 R 7 ,
12) —C(O)OR 6 , or
13) C 3 -C 6 cycloalkyl;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is independently 0, 1, 2, 3 or 4;
q is 1 or 2;
r is 0 to 5;
s is independently 0, 1, 2 or 3;
t is 2, 3, 4, 5 or 6; and
u is 4 or 5;
or a pharmaceutically acceptable salt or stereoisomer thereof.
2. The compound according to claim 1 of the formula B:
wherein:
R 1a , R 1b and R 1c is independently selected from:
a) hydrogen,
b) aryl, heterocycle, C 3 -C 10 cycloalkyl, R 10 O—, —N(R 10 ) 2 or C 2 -C 6 alkenyl, and
c) C 1 -C 6 alkyl unsubstituted or substituted by aryl, heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, R 10 O—, or —N(R 10 ) 2 ;
R 1d is selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, R 10 O—, R 10 C(O)NR 10 —, (R 10 ) 2 N—C(O) NR 10 —, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —,
c) unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 2 -C 6 alkenyl or unsubstituted or substituted C 2 -C 6 alkynyl, wherein the substituent on the substituted C 1 -C 6 alkyl, substituted C 2 -C 6 alkenyl or substituted C 2 -C 6 alkynyl is selected from unsubstituted or substituted aryl, heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 perfluoroalkyl, halogen, R 10 O—, R 4 S(O) m —, R 4 S(O) 2 NR 10 —, R 10 C(O)NR 10 —, (R 10 ) 2 N—C(O)—, CN, (R 10 ) 2 N—C(NR 10 )—, R 10 C(O)—, R 10 OC(O)—, —N(R 10 ) 2 , and R 11 OC(O)—NR 10 —;
R 3a is selected from H and CH 3 ;
R 2a is selected from H;
and C 1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1) aryl,
2) heterocycle,
3) OR 6 ,
4) SR 4 , SO 2 R 4 , or
and any two of R 2a and R 3a are optionally attached to the same carbon atom;
R 4 is selected from:
C 1-4 alkyl and C 3-6 cycloalkyl, unsubstituted or substituted with:
a) C 1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;
R 6 and R 7 are independently selected from H; C 1-6 alkyl, C 3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or two:
a) C 1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
f) —SO 2 R 11 ,
g) N(R 10 ) 2 , or
h) C 3-6 cycloalkyl;
R 8 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 perfluoroalkyl, F, Cl, R 12 O—, R 10 C(O)NR 10 —, CN, NO 2 , (R 10 ) 2 N—C(NR 10 )—, R 10 C(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —, and
c) C 1 -C 6 alkyl substituted by: unsubstituted or substituted aryl, C 1 -C 6 perfluoroalkyl, R 10 O—, R 10 C(O)NR 10 —, (R 10 ) 2 N—C(NR 10 )—, R 10 C(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —;
R 9a is selected from hydrogen, C 1 -C 6 alkyl and C 1 -C 6 perfluoroalkyl;
R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and unsubstituted or substituted aryl;
R 11 is independently selected from C 1 -C 6 alkyl and unsubstituted or substituted aryl;
R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, unsubstituted or substituted benzyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, and C 1 -C 6 alkyl substituted with unsubstituted or substituted aryl or unsubstituted or substituted heterocycle;
A 1 is selected from a bond, —N(R 10 )—, S(O) m and O;
G 1 , G 2 and G 3 are independently selected from H 2 and O;
V is selected from:
a) heterocycle selected from pyridinyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl and isoquinolinyl, and
b) aryl;
X is selected from a bond, —C(═O)—, —NR 10 C(O)—, —OC(O)— or —S(═O) m ;
Y is selected from a bond, —C(═O)—, —C(O)NR 10 —, —C(O)O—, or —S(═O) m ;
Z 1 is selected from unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted aryl or substituted heterocycle is independently substituted with one or two of:
1) C 1-8 alkyl, C 2-8 alkenyl or C 2-8 alkynyl, unsubstituted or substituted with:
a) C 1-4 alkoxy,
b) NR 6 R 7 ,
c) C 3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
f) —S(O) m R 4 ,
g) —C(O)NR 6 R 7 , or
h) C 1-4 perfluoroalkyl;
2) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle,
3) halogen,
4) OR 6 ,
5) NR 6 R 7 ,
6) CN,
7) NO 2 ,
8) CF 3 ,
9) —S(O) m R 4 ,
10) —OS(O) 2 R 4 ,
11) —C(O)NR 6 R 7 ,
12) —C(O)OR 6 , or
13) C 3 -C 6 cycloalkyl;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
r is 0 to 5; and
s is independently 0, 1, 2 or 3;
or a pharmaceutically acceptable salt or stereoisomer thereof.
3. The compound according to claim 2 of the formula C:
wherein:
R 1a , R 1b and R 1c is independently selected from:
a) hydrogen,
b) aryl, heterocycle, C 3 -C 10 cycloalkyl, R 10 O—, —N(R 10 ) 2 or C 2 -C 6 alkenyl, and
c) C 1 -C 6 alkyl unsubstituted or substituted by aryl, heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, R 10 O—, or —N(R 10 ) 2 ;
R 1d is selected from:
a) hydrogen,
b) aryl, heterocycle, C 3 -C 10 cycloalkyl, R 10 O—, —N(R 10 ) 2 or C 2 -C 6 alkenyl, and
c) C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, unsubstituted or substituted by aryl, heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, R 10 O—, or —N(R 10 ) 2 ;
R 3a is selected from H and CH 3 ;
R 2a is selected from H;
and C 1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1) aryl,
2) heterocycle,
3) OR 6 ,
4) SR 4 , SO 2 R 4 , or
and any two of R 2a and R 3a are optionally attached to the same carbon atom;
R 4 is selected from C 1-4 alkyl and C 3-6 cycloalkyl, unsubstituted or substituted with:
a) C 1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;
R 6 and R 7 are independently selected from:
a) hydrogen,
b) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 10 C(O)— or R 10 OC(O)— and
c) C 1 -C 6 alkyl substituted by C 1 -C 6 perfluoroalkyl, R 10 O—, R 10 C(O)NR 10 —, (R 10 ) 2 N—C(NR 10 )—, R 10 C(O)—, R 10 OC(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —;
R 8 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 perfluoroalkyl, F, Cl, R 12 O—, R 10 C(O)NR 10 —, CN, NO 2 , (R 10 ) 2 N—C(NR 10 )—, R 10 C(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —, and
c) C 1 -C 6 alkyl substituted by unsubstituted or substituted aryl, C 1 -C 6 perfluoroalkyl, R 10 —, R 10 C(O)NR 10 —, (R 10 ) 2 N—C(NR 10 )—, R 10 C(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —;
R 9a is selected from hydrogen, C 1 -C 6 alkyl and C 1 -C 6 perfluoroalkyl;
R 10 and R 12 are independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and unsubstituted or substituted aryl;
R 11 is independently selected from C 1 -C 6 alkyl and unsubstituted or substituted aryl;
A 1 is selected from a bond, —N(R 10 )—, S(O) m and O;
X is selected from a bond, —C(═O)—, —NR 10 C(O)—, —OC(O)— or —S(═O) m ;
Y is selected from a bond, —C(═O)—, —C(O)NR 10 —, —C(O)O—, or —S(═O) m ;
Z 1 is selected from unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted aryl or substituted heterocycle is substituted with one or two of:
1) C 1-4 alkyl, unsubstituted or substituted with:
a) C 1-4 alkoxy,
b) NR 6 R 7 ,
c) C 3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
f) —S(O) m R 4 , or
g) —C(O)NR 6 R 7 ,
2) aryl or heterocycle,
3) halogen,
4) OR 6 ,
5) NR 6 R 7 ,
6) CN,
7) NO 2 ,
8) CF 3 ,
9) —S(O) m R 4 ,
10) —C(O)NR 6 R 7 , or
11) C 3 -C 6 cycloalkyl;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
r is 0 to 5; and
s is independently 0, 1, 2 or 3 ;
or a pharmaceutically acceptable salt or stereoisomer thereof.
4. The compound according to claim 3 of the formula D:
wherein:
R 1b and R 1c is independently selected from:
a) hydrogen,
b) aryl, heterocycle, C 3 -C 10 cycloalkyl, R 10 O— —N(R 10 ) 2 , and
c) C 1 -C 6 alkyl unsubstituted or substituted by aryl, heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, R 10 O—, or —N(R 10 ) 2 ;
R 1d is selected from:
a) hydrogen,
b) aryl, heterocycle, C 3 -C 10 cycloalkyl, R 10 O— or —N(R 10 ) 2 , and
c) C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, unsubstituted or substituted by aryl, heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, R 10 O—, or —N(R 10 ) 2 ;
R 3a is selected from H and CH 3 ;
R 2a is selected from H;
and C 1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1) aryl,
2) heterocycle,
3) OR 6 ,
4) SR 4 , SO 2 R 4 , or
and any two of R 2 and R 3 are optionally attached to the same carbon atom;
R 4 is selected from C 1-4 alkyl and C 3-6 cycloalkyl, unsubstituted or substituted with:
a) C 1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;
R 6 and R 7 are independently selected from H; C 1-6 alkyl, C 3-6 cycloalkyl, aryl, aroyl, arylsulfonyl, unsubstituted or substituted with one or two:
a) C 1-4 alkoxy,
b) aryl,
c) halogen,
d) HO,
f) —SO 2 R 11 ,
g) N(R 10 ) 2 ,
h) C 3-6 cycloalkyl; or
R 8 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 perfluoroalkyl, F, Cl, R 12 O—, R 10 C(O)NR 10 —, CN, NO 2 , (R 10 ) 2 N—C(NR 10 )—, R 10 C(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —, and
c) C 1 -C 6 alkyl substituted by unsubstituted or substituted aryl, C 1 -C 6 perfluoroalkyl, R 10 O—, R 10 C(O)NR 10 —, (R 10 ) 2 N—C(NR 10 )—, R 10 C(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —;
R 9a is selected from hydrogen, C 1 -C 6 alkyl and C 1 -C 6 perfluoroalkyl;
R 10 and R 12 are independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and unsubstituted or substituted aryl;
R 11 is independently selected from C 1 -C 6 alkyl and unsubstituted or substituted aryl;
A 11 is selected from a bond, —N(R 10 )—, S(O) m and O;
X is selected from a bond, —C(═O)—, —NR 10 OC(O)—, —OC(O)— or —(═O) m ;
Y is selected from a bond, —C(═O)—, —C(O)NR 10 —, —C(O)O—, or —S(═O) m ;
Z 1 is selected from unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted aryl or substituted heterocycle is substituted with one or two of:
1) C 1-8 alkyl, C 2-8 alkenyl or C 2 8 alkynyl, unsubstituted or substituted with:
a) C 1-4 alkoxy,
b) NR 6 R 7 ,
c) C 3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
f) —S(O) m R 4 ,
g) —C(O)NR 6 R 7 , or
h) C 1-4 perfluoroalkyl;
2) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle,
3) halogen,
4) OR 6 ,
5) NR 6 R 7 ,
6) CN,
7) NO 2 ,
8) CF 3 ,
9) —S(O) m R 4 ,
10) —OS(O) 2 R 4 ,
11) —C(O)NR 6 R 7 ,
12) —C(O)OR 6 , or
13) C 3 -C 6 cycloalkyl;
m is 0, 1 or 2;
p is independently 0, 1, 2, 3 or 4;
r is 0 to 5; and
s is independently 0, 1, 2 or 3;
or a pharmaceutically acceptable salt or stereoisomer thereof.
5. The compound according to claim 3 of the formula E:
wherein:
R 1b and R 1c is independently selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, R 10 O—, —N(R 10 ) 2 or C 2 -C 6 alkenyl, and
c) C 1 -C 6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 10 O—, or —N(R 10 ) 2 ;
R 1d is selected from:
a) hydrogen,
b) aryl, heterocycle, C 3 -C 10 cycloalkyl or C 2 -C 6 alkenyl, and
c) C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, unsubstituted or substituted by aryl, heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, R 10 O—, or —N(R 10 ) 2 ;
R 3a is selected from H and CH 3 ;
R 2a is selected from H;
and C 1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1) aryl,
2) heterocycle,
3) OR 6 ,
4) SR 4 , SO 2 R 4 , or
and any two of R 2a and R 3a are optionally attached to the same carbon atom;
R 4 is selected from C 1-4 alkyl and C 3-6 cycloalkyl, unsubstituted or substituted with:
a) C 1-4 alkoxy,
b) fluoro, or
c) aryl or heterocycle;
R 6 and R 7 are independently selected from H; C 1-6 alkyl, C 3-6 cycloalkyl, aryl, aroyl, arylsulfonyl, unsubstituted or substituted with one or two:
a) C 1-4 alkoxy,
b) aryl,
c) halogen,
d) HO,
f) —SO 2 R 11 ,
g) N(R 10 ) 2 , or
h) C 3-6 cycloalkyl,
R 8 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 perfluoroalkyl, F, Cl, R 12 O—, R 10 C(O)NR 10 —, CN, NO 2 , (R 10 ) 2 N—C(NR 10 )—, R 10 C(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —, and
c) C 1 -C 6 alkyl substituted by unsubstituted or substituted aryl, C 1 -C 6 perfluoroalkyl, R 10 O—, R 10 C(O)NR 10 —, (R 10 ) 2 N—C(NR 10 )—, R 10 C(O)—, —N(R 10 ) 2 , or R 11 OC(O)NR 10 —;
R 9a is selected from hydrogen, C 1 -C 6 alkyl and C 1 -C 6 perfluoroalkyl;
R 10 and R 12 are independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and unsubstituted or substituted aryl;
R 11 is independently selected from C 1 -C 6 alkyl and unsubstituted or substituted aryl;
A 1 is selected from a bond, —N(R 10 )—, S(O) m and O;
X is selected from a bond, —C(═O)—, —NR 10 C(O)—, —OC(O)— or —S(═O) m ;
Y is selected from a bond, —C(═O)—, —C(O)NR 10 —, —C(O)O—, or —S(═O) m ;
Z 1 is selected from unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted aryl or substituted heterocycle is substituted with one or two of:
1) C 1-8 alkyl, C 2-8 alkenyl or C 2-8 alkynyl, unsubstituted or substituted with:
a) C 1-4 alkoxy,
b) NR 6 R 7 ,
C) C 3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
f) —S(O) m R 4 ,
g) —C(O)NR 6 R 7 , or
h) C 1-4 perfluoroalkyl;
2) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle,
3) halogen,
4) OR 6 ,
5) NR 6 R 7 ,
6) CN,
7) NO 2 ,
8) CF 3 ,
9) —S(O) m R 4 ,
10) —OS(O) 2 R 4 ,
11) —C(O)NR 6 R 7 ,
12) —C(O)OR 6 , or
13) C 3 -C 6 cycloalkyl;
m is 0, 1 or 2;
p is independently 1, 2, 3 or 4;
r is 0 to 5; and
s is independently 0, 1, 2 or 3;
or a pharmaceutically acceptable salt or stereoisomer thereof.
6. A compound which is selected from:
14-amino-14-(1-methyl-1H-imidazol-5-yl)-8-oxa-2-thia-1,18-diazatetracyclo[16.2.2.1 3,7 .1 9,13 ]tetracosa-3(24),4,6,9(23),10,12-hexaene-10-carbonitrile 2,2-dioxide;
14-amino-4-chloro-14-(1-methyl-1H-imidazol-5-yl)—20-oxo-8-oxa-1,18-diazatetracyclo[16.2.2.1 3,7 .1 9,13 ]tetracosa-3(24),4,6,9(23),10,12-hexaene-10-carbonitrile;
18-Bromo-8-[5-(1-methyl-1H-imidazolyl)]-8-methyl-3,7:1,17-dimetheno-11H-10,14-dioxo-12,15-ethano-16H-2-oxa-9,10:13,14-tetrahydro-[9,12,15]triaza-cycloeicosene-4-carbonitrile;
18-Chloro-8-[5-(1-methyl-1H-imidazolyl)]-8-methyl-3,7:1,17-dimetheno-11H-10,14-dioxo-12,15-ethano-16H-2-oxa-9,10:13,14-tetrahydro-[9,12,15]triaza-cycloeicosene-4-carbonitrile;
or a pharmaceutically acceptable salt or stereoisomer thereof.
7. The compound according to claim 6 which is
14-amino-14-(1-methyl-1H-imidazol-5-yl)-8-oxa-2-thia-1,18-diazatetracyclo[16.2.2.1 3,7 .1 9,13 ]tetracosa-3(24),4,6,9(23),10,12-hexaene-10-carbonitrile 2,2-dioxide
or a pharmaceutically acceptable salt or stereoisomer thereof.
8. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 1 .
9. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 3 .
10. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 6 .
11. A method for treating blindness related to retinal vascularization which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of claim 8 .
12. A method for treating infections from hepatitis delta which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of claim 8 .
13. A method for preventing restenosis after percutaneous transluminal coronary angioplasty which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of claim 8 .
14. A method for treating polycystic kidney disease which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of claim 8 .
15. A method of conferring radiation sensitivity on a tumor cell using a therapeutically effective amount of a composition of claim 8 in combination with radiation therapy.
16. A method of using a therapeutically effective amount of a composition of claim 8 in combination with an antineoplastic to treat cancer.
17. A method according to claim 16 wherein the antineoplastic is paclitaxel.
18. A process for making a pharmaceutical composition comprising combining a compound of claim 1 and a pharmaceutically acceptable carrier.Cited by (0)
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